title: Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism.
abstract: Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.forename: Marina
authors.initials: M
authors.lastname: Picillo
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Josja
authors.initials: J
authors.lastname: Graafland
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Fengping
authors.initials: F
authors.lastname: Xu
authors.forename: Roberto
authors.initials: R
authors.lastname: Erro
authors.forename: Marianna
authors.initials: M
authors.lastname: Amboni
authors.forename: Sabina
authors.initials: S
authors.lastname: Pappatà
authors.forename: Mario
authors.initials: M
authors.lastname: Quarantelli
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Hsin F
authors.initials: HF
authors.lastname: Chien
authors.forename: Egberto R
authors.initials: ER
authors.lastname: Barbosa
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D034021:Auxilins / Q000378:metabolism; D002648:Child; D003072:Cognition Disorders; D003241:Consanguinity; D004421:Dystonia; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D007558:Italy; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics*; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011859:Radiography; D017422:Sequence Analysis, DNA; D055815:Young Adult; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D034021:Auxilins; D007980:Levodopa; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: PINK1; Parkinsonism; SYNJ1; dementia; dystonia; gene; mutation